Skin Biopsy

Skin biopsy Electron Microscopy (EM)

Skin is a tissue that is relatively commonly biopsied because: 1. It is reasonably straight-forward to get to, 2. Biopsy is relatively risk-free compared to other tissues or organs, 3. For many skin diseases it is a means whereby the affecting disorder is diagnoseable by conventional Hematoxylin and Eosin (H&E) stained sections viewed by light microscopy (also known as histology, histopathology, micro-anatomical or surgical pathology).

However, if it isn’t clear what the diagnosis is by conventional histology of the skin biopsy, EM can be used as well.

If it is anticipated that EM might be useful for diagnosis, then a skin biopsy is preserved, or fixed, in buffered glutaraldehyde - whilst if EM isn’t anticipated that it might be necessary, then tissue can be retrieved from the conventionally formalin fixed, and paraffin processed biopsy.  If it is considered that EM may be needed, but it is unlikely, then a small portion of the biopsy may be kept back in formalin – but this is rarely done.

If there is uncertainty on what the type of tumour biopsied in the skin is after histology has been done, then EM can be helpful. EM isn’t typically relied upon to decide if a tumour is malignant or benign. EM was the go-to technique prior to the early 1990’s – but due to improvements in labelled monoclonal antibody techniques also known as immunohistochemistry (IHC), that is no longer the case.

Skin biopsies of viral infections like: Pox viruses, Papilloma viruses, Herpes simplex virus, Herpes Varicella-zoster virus (image VZV) or Coxsackie viruses can be diagnosed by electron microscopy. If a skin blister is present and an infectious cause is considered, then EM of the fluid with negative staining, can be a rapid way of distinguishing between these groups of viruses.

EM and the specialist ancillary technology of x-ray microanalysis or Energy Dispersive Analysis of X-rays (EDAX) is useful to identify any inorganic foreign material eg gadolinium from MRI contrast, silver workers pigmentation (image Argyria) etc.

Amyloid (image Amyloid), of whatever type, can be diagnosed by histology of the skin biopsy stained with Sirius or Congo Red. But, if there is uncertainty whether what is seen is a false positive or false negative test, then EM can help remove that doubt.

Scanning electron microscopy (SEM) can be useful when looking at hair samples eg Menkes disease (image Menkes).

Until approximately 2018, when second also known as next generation gene sequencing (NGS) became available in hospitals and less expensive, EM of glutaraldehyde fixed skin biopsies were routinely used for diagnosis of a moderate number of inherited disorders, irrespective of whether they noticeably affected the skin or not.

Examples of inherited diseases that don’t primarily affect the skin that used to be routinely diagnosed by electron microscopy are: lysosomal storage disorders, Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), pseuoxanthoma elasticum (PXE) and Ehlers-Danlos syndromes (image classical Ehlers-Danlos syndrome).

Examples of inherited diseases that do primarily affect the skin and until NGS were routinely looked at by EM are: ichthyosis or disorders of cornification, inherited bullous disorders and cutis laxa.

EM can still be used to help diagnose the above inherited conditions if the molecular genetic analysis fails to find a known pathogenic mutation. Although in these cases the findings may still leave questions unanswered. Very occasionally EM can uncover unexpected and significant changes.

EM of skin is still used in research settings where a pathogenic mutation is known but the cellular changes are not fully characterised – in which case, ethics committee consent has to be given, along with patient consent, for the research.

Other techniques more typically used in a research setting can be used on skin biopsies, such as immunogold labelling, tilt and serial block face scanning electron microscopy tomography and 3D reconstruction.


TEM Varicella Zoster Virus in Conjunctiva - Formalin fixed paraffin processed



TEM Classical Ehlers-Danlos Syndrome dermal collagen



SEM Hair Menkes Syndrome



TEM Cutaneous Amyloid - Unknown hereditary type